Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses

ABSTRACT

Disclosed are nitrosated and/or nitrosylated phosphodiesterase inhibitors having the formula NOn-PDE inhibitor where n is 1 or 2. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The invention also provides a composition comprising a therapeutically effective amount of an phosphodiesterase inhibitor (PDE inhibitor), which can optionally be substituted with at least one NO or NO2 moiety, and one to ten fold molar excess of a compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO.) or which stimulates endogenous EDRF production. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The invention also provides methods for treating sexual dysfunctions in males and females.

RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 09/145,142 filed Sep.1, 1998, issued as U.S. Pat. No. 5,958,926, which is acontinuation-in-part of U.S. application Ser. No. 08/740,764, filed Nov.1, 1996, issued as U.S. Pat. No. 5,874,437; and which is acontinuation-in-part of PCT/US97/19870 filed Oct. 31, 1997.

FIELD OF THE INVENTION

This invention generally relates to pharmaceuticals and morespecifically to methods and compositions for treating sexualdysfunctions in males and females.

BACKGROUND OF THE INVENTION

Adequate sexual function is a complex interaction of hormonal events andpsychosocial relationships. There are four stages to sexual response asdescribed in the International Journal of Gynecology & Obstetrics,51(3):265-277 (1995). The first stage of sexual response is desire. Thesecond stage of sexual response is arousal. Both physical and emotionalstimulation may lead to breast and genital vasodilation and clitoralengorgement (vasocongestion). In the female, dilation and engorgement ofthe blood vessels in the labia and tissue surrounding the vagina producethe “orgasmic platform,” an area at the distal third of the vagina whereblood becomes sequestered. Localized perivaginal swelling and vaginallubrication make up the changes in this stage of sexual response.Subsequently, ballooning of the proximal portion of the vagina andelevation of the uterus occurs. In the male, vasodilation of thecavernosal arteries and closure of the venous channels that drain thepenis produce an erection. The third stage of sexual response is orgasm,while the fourth stage is resolution. Interruption or absence of any ofthe stages of the sexual response cycle can result in sexualdysfunction. One study found that 35% of males and 42% of femalesreported some form of sexual dysfunction. Read et al, J. Public HealthMed., 19(4):387-391 (1997).

In both pre-menopausal and menopausal females, sexual dysfunction caninclude, for example, sexual pain disorders, sexual desire disorders,sexual arousal dysfunction, orgasmic dysfunction, dyspareunia, andvaginismus. Sexual dysfunction can be caused, for example, by pregnancy,menopause, cancer, pelvic surgery, chronic medical illness ormedications.

Erectile dysfunction is a widespread disorder that is thought to affectabout 10% to 15% percent of adult men. A number of causes of erectileinsufficiency, in addition to anatomical deficiencies of the penis orscrotum that preclude an erection sufficient for vaginal penetration,have been identified. Causes of erectile dysfunction can be categorizedas psychogenic, neurogenic, endocrinologic, drug-induced, orvasculogenic and in any individual suffering from erectile dysfunctionthere may be more than one cause.

Psychogenic impotence is often the result of anxiety or depression, withno apparent somatic or organic impairment Neurogenic impotence may arisefrom, for example, surgery or a pelvic injury, involving the nervoussystem affecting the penis. Erectile dysfunction which is endocrinologicin origin is most often associated with the disorders hypo- orhypergonadotropic hypogonadism and hyperprolactinemia.

Vasculogenic impotence is thought to be the most frequent cause ofimpotence accounting for approximately fifty percent of all cases oforganic impotence. In these cases, the erectile dysfunction may beattributed to alterations in the flow of blood to and from the penis.Atherosclerotic or traumatic arterial occlusive disease to the arterieswhich supply blood to the penis can lead to a decrease in the rigidityof the erect penis as well as increase the time to achieving maximalerection. In still other cases, there is leakage from veins in the penissuch that sufficient pressure for an erection can be neither obtainednor maintained.

There is also a high incidence of erectile insufficiency amongdiabetics, particularly those with insulin-dependent diabetes mellitus.Erectile dysfunction in diabetics is often classified as “diabetogenic,”although the underlying dysfunction is usually neurogenic, but may bevasculogenic or neurogenic and vasculogenic. About half of diabeticmales suffer from erectile insufficiency, and about half of the cases ofneurogenic impotence are in diabetics.

Erectile insufficiency is sometimes a side effect of certain drugs, suchas beta-antagonists that are administered to reduce blood pressure inpersons suffering from hypertension, or drugs administered to treatdepression or anxiety. Excessive alcohol consumption has also beenlinked to erectile insufficiency. These forms of erectile insufficiencymay be regarded as a subset of neurogenic or psychogenic insufficiency.

A number of methods to treat impotence are available. These treatmentsinclude pharmacological treatments, surgery and, in cases of psychogenicdysfunction, psychological counseling is sometimes effective.Psychogenic impotence often can be cured by counseling coupled with ademonstration to the patient that he is capable of having a fullerection by inducing such an erection from one to a few times in thepatients. Insufficiency due to excessive alcohol consumption issometimes cured by reducing or eliminating such consumption.

In the rare cases where the insufficiency is untreatable because ofvenous leakage, surgery can usually be used to repair the venous lesionand thereby either cure the insufficiency or, if there remains anerectile insufficiency after repair of the venous lesion, render theinsufficiency amenable to treatment by pharmacological methods. Also,penile implants, which provide a mechanic means to produce an erectionsufficient for vaginal penetration, are widely used to treat impotence.In recent years, implants have been used, especially in cases wherepharmacological intervention is ineffective, which are usually cases ofsevere vasculogenic impotence. Treatment of impotence with penileimplants, however, entails serious disadvantages. Such treatmentrequires surgery and necessitates total destruction of the erectiletissues of the penis, forever precluding normal erection.

Pharmacological methods of treatment are also available. Such methods,however, have not proven to be highly satisfactory or withoutpotentially severe side-effects. Papaverine is now widely used to treatimpotence, although papaverine is ineffective in overcoming impotencedue, at least in part, to severe atherosclerosis. Papaverine iseffective in cases where the dysfunction is psychogenic or neurogenicand severe atherosclerosis is not involved. Injection of papaverine, aphosphodiesterase inhibitor and a smooth muscle relaxant, orphenoxybenzamine, a non-specific antagonist and hypotensive, into corpuscavernosum has been found to cause an erection sufficient for vaginalpenetration, however, these treatments are not without the serious andoften painful side effect of priapism. Also, in cases where severeatherosclerosis is not a cause of the dysfunction, intracavernosalinjection of phentolamine, an α-adrenergic antagonist, causes anerection sufficient for vaginal penetration. The resulting erection isone of significantly shorter duration than that induced byintracavernosal injection of papaverine or phenoxybenzamine and oftentimes is of such short duration that satisfactory sexual relations aredifficult or impossible. As an alternative or, in some cases an adjunctto phosphodiesterase inhibition or α-adrenergic blockade for thetreatment of erectile dysfunction, prostaglandin E1 (PGE1) has beenadministered via intracavernosal injection. A major side effectfrequently associated with intracorprally delivered PGE1 is penile painand burning.

Thus, there is a need in the art for treatments of male and femalesexual dysfunctions, including treatments without the undesirable sideeffects of those agents currently used. The present invention isdirected to these, as well as other, important ends.

SUMMARY OF THE INVENTION

Nitric oxide (NO) has been shown to mediate a number of actionsincluding the bactericidal and tumoricidal actions of macrophages andblood vessel relaxation of endothelial cells. NO and NO donors have alsobeen implicated as mediators of nonvascular smooth muscle relaxation. Asdescribed herein, this effect includes the dilation of the corpuscavernosum smooth muscle, an event involved in the sexual responseprocess in both males and females. However, the effects of modifiedphosphodiesterase inhibitors which are directly or indirectly linkedwith a nitric oxide adduct have not been investigated.

In the process of arriving at the present invention it was recognizedthat the risk of toxicities and adverse effects that are associated withhigh doses of phosphodiesterase inhibitors can be avoided by the use ofsuch phosphodiesterase inhibitors when nitrosated or nitrosylated. Suchtoxicities and adverse effects include hypotension, syncope, as well aspriapism. The smooth muscle relaxant properties of phosphodiesteraseinhibitors and of compounds that donate, release or transfer nitrogenmonoxide or elevate levels of endogenous endothelium-derived relaxingfactor (EDRF) work together to permit the same efficacy with lower dosesof the phosphodiesterase inhibitors.

Accordingly, in one aspect the invention provides novel nitrosated andnitrosylated phosphodiesterase inhibitors: NO_(n)-PDE inhibitor where nis 1 or 2. The phosphodiesterase inhibitor can be nitrosylated ornitrosated through sites such as oxygen (hvdroxyl condensation), sulfur(sulfhydryl condensation), carbon and nitrogen. The invention alsoprovides compositions comprising such compounds in a pharmaceuticallyacceptable carrier.

In another aspect the invention provides compositions comprising atherapeutically effective amount of at least one phosphodiesteraseinhibitor (PDE inhibitor), which can optionally be substituted with atleast one NO or NO₂ moiety, and one to ten fold molar excess of at leastone compound that donates, transfers or releases nitrogen monoxide as acharged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as theneutral species, nitric oxide (NO•), or elevates levels of endogenousEDRF. The invention also provides compositions comprising such compoundsin a pharmaceutically acceptable carrier.

In another aspect, the invention provides methods for treating and/orpreventing sexual dysfunctions or improving and/or enhancing sexualresponses in humans, including males and females, which comprisesadministering to an individual in need thereof a therapeuticallyeffective amount of at least one nitrosated or nitrosylated PDEinhibitor.

In another aspect, the invention provides methods for treating and/orpreventing sexual dysfunctions or improving and/or enhancing sexualresponses in humans, including males and females, which comprisesadministering to an individual in need thereof a composition comprisinga therapeutically effective amount of at least one PDE inhibitor whichcan optionally be substituted with at least one NO or NO₂ moiety, and atleast one compound that donates, transfers or releases nitric oxide as acharged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as theneutral species, nitric oxide (NO•), or that elevates levels ofendogenous EDRF. The PDE inhibitor or PDE inhibitor directly orindirectly linked to at least one NO or NO₂ group, and nitric oxidedonor can be administered separately or as components of the samecomposition.

The nitrosated or nitrosylated PDE inhibitor and the compound thatdonates, transfers or releases nitric oxide and/or stimulates endogenousproduction of NO or EDRF in vivo can be administered separately or ascomponents of the same composition in one or more pharmaceuticallyacceptable carriers.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not intended to limit the scope of the invention as defined bythe claims.

FIG. 1 shows a synthetic scheme for the preparation of nitritecontaining substituted benzene derivatives.

FIG. 2 shows a synthetic scheme for the preparation of nitrosothiolcontaining substituted benzene derivatives.

FIG. 3 shows a synthetic scheme for the preparation of nitratecontaining substituted benzene derivatives.

FIG. 4 shows a synthetic scheme for the preparation of nitritecontaining imidazo[2,1-b]quinazoline derivatives.

FIG. 5 shows a synthetic scheme for the preparation of nitrosothiolcontaining imidazo[2,1-b]quinazoline derivatives.

FIG. 6 shows a synthetic scheme for the preparation of nitratecontaining imidazo[2,1-b]quinazoline derivatives.

FIG. 7 shows a synthetic scheme for the preparation of nitritecontaining purine-6-one derivatives.

FIG. 8 shows a synthetic scheme for the preparation of nitrosothiolcontaining purine-6-one derivatives.

FIG. 9 shows a synthetic scheme for the preparation of nitratecontaining purine-6-one derivatives.

FIG. 10 shows a synthetic scheme for the preparation of nitritecontaining pyrimidin-4-one derivatives.

FIG. 11 shows a synthetic scheme for the preparation of nitrosothiolcontaining pyrimidin-4-one derivatives.

FIG. 12 shows a synthetic scheme for the preparation of nitratecontaining pyrimidin-4-one derivatives.

FIG. 13 shows a synthetic scheme for the preparation of nitritecontaining 2-pyridone derivatives.

FIG. 14 shows a synthetic scheme for the preparation of nitrosothiolcontaining 2-pyridone derivatives.

FIG. 15 shows a synthetic scheme for the preparation of nitratecontaining 2-pyridone derivatives.

FIG. 16 shows a synthetic scheme for the preparation of nitritecontaining purine-2,6-dione derivatives.

FIG. 17 shows a synthetic scheme for the preparation of nitrosothiolcontaining purine-2,6-dione denvatives.

FIG. 18 shows a synthetic scheme for the preparation of nitratecontaining purine-2,6-dione derivatives.

FIG. 19 shows a synthetic scheme for the preparation of nitritecontaining quinoline derivatives.

FIG. 20 shows a synthetic scheme for the preparation of nitrosothiolcontaining quinoline derivatives.

FIG. 21 shows a synthetic scheme for the preparation of nitratecontaining quinoline derivatives.

FIG. 22 shows a synthetic scheme for the preparation of nitritecontaining substituted pyridine derivatives.

FIG. 23 shows a synthetic scheme for the preparation of nitrosothiolcontaining substituted pyridine derivatives.

FIG. 24 shows a synthetic scheme for the preparation of nitratecontaining substituted pyridine derivatives.

FIG. 25 shows a synthetic scheme for the preparation of nitritecontaining benzo [c] [1,6] naphthyridine derivatives.

FIG. 26 shows a synthetic scheme for the preparation of nitrosothiolcontaining benzo[c] [1,6] naphthyridine derivatives.

FIG. 27 shows a synthetic scheme for the preparation of nitratecontaining benzo[c] [1,6] naphthyridine derivatives.

FIG. 28 shows a synthetic scheme for the preparation of nitritecontaining 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido [5,4-d]pyrimidine derivatives.

FIG. 29 shows a synthetic scheme for the preparation of nitrosothiolcontaining 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido [5,4-d]pyrimidine derivatives.

FIG. 30 shows a synthetic scheme for the preparation of nitratecontaining 2,6-dihydroxyalkylamino-4,8-dipiperidino pyrimido [5,4-d]pyrimidine derivatives.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions may be used throughout the specification.

The term “lower alkyl” as used herein refers to branched or straightchain alkyl groups comprising one to ten carbon atoms, including methyl,ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.

The term “alkoxy” as used herein refers to R₅₀O— wherein R₅₀ is a loweralkyl group as defined herein. “Alkoxy groups” include, for example,methoxy, ethoxy, t-butoxy and the like.

The term “alkoxyalkyl” as used herein refers to an alkoxy group aspreviously defined appended to an alkyl group as previously defined.Examples of alkoxyalkyl include, but are not limited to, methoxymethyl,methoxyethyl, isopropoxymethyl and the like.

The term “hydroxy” as used herein refers to —OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy group aspreviously defined appended to a lower alkyl group as previouslydefined.

The term “alkenyl” as used herein refers to a branched or straight chainC₂-C₁₀ hydrocarbon which also comprises one or more carbon-carbon doublebonds.

The term “amino” as used herein refers to —NH₂.

The term “nitrate” as used herein refers to —O—NO₂.

The term “alkylamino” as used herein refers to R₅₀NH— wherein R₅₀ is asdefined in the specification. Alkylamino groups include, for example,methylamino, ethylamino, butylamino, and the like.

The term “dialkylamino” as used herein refers to R₅₂R₅₃N— wherein R₅₂and R₅₃ are independently selected from lower alkyl groups as definedherein. Dialkylamino groups include, for example dimethylamino,diethylamino, methyl propylamino and the like.

The term “nitro” as used herein refers to the group —NO₂ and“nitrosated” refers to compounds that have been substituted therewith.

The term “nitroso” as used herein refers to the group —NO and“nitrosylated” refers to compounds that have been substituted therewith.

The term “aryl” as used herein refers to a mono- or bi-cycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl,and the like. Aryl groups (including bicyclic aryl groups) can beunsubstituted or substituted with one, two or three substituentsindependently selected from lower alkyl, haloalkyl, alkoxy, amino,alkylamino, dialkylamino, hydroxy, halo, and nitro. In addition,substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term “alkylaryl” as used herein refers to a lower alkyl radical towhich is appended an aryl group. Arylalkyl groups include, for example,benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl andthe like.

The term “arylalkoxy” as used herein refers to an alkoxy radical towhich is appended an aryl group. Arylalkoxy groups include, for example,benzyloxy, phenylethoxy, chlorophenylethoxy and the like.

The term “cycloalkyl” as used herein refers to an alicyclic groupcomprising from about 3 to about 7 carbon atoms including, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike.

The term “bridged cycloalkyl” as used herein refers to two or morecycloalkyl radicals fused via adjacent or non-adjacent carbon atoms,including, but not limited to, adamantyl and decahydronapthyl.

The term “cycloalkoxy” as used herein refers to R₅₄O— wherein R₅₄ iscycloalkyl as defined in this specification. Representative examples ofalkoxy groups include cyclopropoxy, cyclopentyloxy, and cyclohexyloxyand the like.

The term “arylthio” as used herein refers to R₅₅S— wherein R₅₅ is anaryl group as defined herein.

The term “alkylsulfinyl” as used herein refers to R₅₀—S(O)₂— wherein R₅₀is as defined in this specification.

The term “caboxamido” as used herein refers to —C(O)NH₂.

The term “carbamoyl” as used herein refers to —O—C(O)NH₂.

The term “carboxyl” as used herein refers to —CO₂H.

The term “carbonyl” as used herein refers to —C(O)—.

The term “halogen” or “halo” as used herein refers to I, Br, Cl, or F.

The term “haloalkyl” as used herein refers to a lower alkyl radical towhich is appended one or more halogens. Representative examples ofhaloalkyl group include trigluoromethyl, chloromethyl, 2-bromobutyl,1-bromo-2-chloro-pentyl and the like.

The term “haloalkoxy” as used herein refers to a haloalkyl radical asdefined herein to which is appended an alkoxy group as defined herein.Representative examples of haloalkoxy groups include1,1,1-trichloroethoxy, 2-bromobutoxy and the like.

The term “heteroayl” as used herein refers to a mono-or bi-cyclic ringsystem containng one or two aromatic rings and containing at least onenitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroaryl groups(including bicyclic heteroaryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino,hydroxy, halo and nitro. Examples of heteroaryl groups include, but arenot limited to, pyridine pyrazine, pyrimidine, pyridazine, pyrazole,triazole, thiazole, isothiazole, benzothiazole, benzoxazole,thiadiazole, oxazole, pyrrole, imidazole, isoxazole and the like.

The term “heterocyclic ring” as used herein refers to any 3-, 4-, 5-,6-, or 7-membered nonaromatic ring containing at least one nitrogenatom, oxygen atom, or sulfur atom which is bonded to an atom which isnot part of the heterocyclic ring.

The term “arylheterocyclic ring” as used herein refers to a bi- ortri-cyclic ring comprised of an aryl ring as previously defined appendedvia two adjacent carbon atoms of the aryl group to a heterocyclic ringas previously defined.

The term “heterocyclic compounds” as used herein refers to mono- andpoly-cyclic compounds containing at least one heteroaryl or heterocyclicring, as defined herein.

The term “amido” as used herein refers to —NH—C(O)—R₅₆ wherein R₅₆ is alower alkyl, aryl, or hereroaryl group, as defined herein.

The term “alkylamido” as used herein refers to R₅₀N—C(O)—R₅₆ wherein R₅₀is a lower alkyl group as defined herein and R₅₆ is a lower akyl, aryl,or hereroaryl goup, as defined herein.

The term “carboxylic ester” as used herein refers to —C(O)OR₅₀, whereinR₅₀ is a lower alkyl group as defined herein.

The term “carboxylic acid” as used herein refers to —C(O)OH.

The term “phosphoryl” as used herein refers to —P(R₇₀)(R₇₁), wherein R₇₀is a lone pair of electrons, sulfur or oxygen and R₇₁ is independently ahydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy or an aryl.

The term “sexual dysfunction” generally includes any sexual dysfunctionin an animal, preferably a mammal, more preferably a human. The animalcan be male or female. Sexual dysfunction may include, for example,sexual desire disorders, sexual arousal disorders, orgasmic disordersand sexual pain disorders. Female sexual dysfunction refers to anyfemale sexual dysfunction including, for example, sexual desiredisorders, sexual arousal dysfunction, orgasmic dysfunction, sexual paindisorders, dyspareunia, and vaginismus. The female can be pre-menopausalor menopausal. Male sexual dysfunction refers to any male sexualdysfunction including, for example, male erectile dysfunction andimpotence.

While there are obvious differences in the sexual response between malesand females, one common aspect of the sexual response is the erectileresponse. As described in U.S. Pat. No. 5,565,466, the disclosure ofwhich is incorporated herein by reference in its entirety, the erectileresponse in both males and females is the result of engorgement of theerectile tissues of the genitalia with blood caused by the relaxation ofsmooth muscles in the arteries serving the genitalia.

The vasculature which serves erectile tissue in males and females issimilar. In particular, the arterial circulation of the erectile tissuesof the genitalia derives from the common iliac artery which branchesfrom the abdominal aorta. The common iliac artery bifurcates into theinternal and external iliac arteries. The internal pudic artery arisesfrom the smaller of two terminal branches of the anterior trunk of theinternal iliac artery. In the female, the internal pudic artery branchesinto the superficial perineal artery which supplies the labia pudenda.The internal pudic artery also branches into the artery of the bulbwhich supplies the bulbi vestibuli and the erectile tissue of thevagina. The artery of the corpus cavernosum, another branch of theinternal pudic artery supplies the cavernous body of the clitoris. Stillanother branch of the internal pudic artery is the arteria dorsalisclitoridis which supplies the dorsum of the clitoris and terminates inthe glans and membranous folds surrounding the clitoris which correspondto the prepuce of the male.

In the male, the internal pudic artery branches into the dorsal arteryof the penis (which itself branches into a left and right branch) andthe artery of the corpus cavernosum, all of which supply blood to thecorpus cavernosum. The dorsal artery of the penis is analogous to theartery dorsalis clitoridis in the female, while the artery of the corpuscavernosum in the male is analogous to the artery of the same name inthe female.

The male erectile response is regulated by the autonomic nervous systemwhich controls blood flow to the penis via the interaction of peripheralnerves associated with the arterial vessels in and around the corpuscavernosum. In the non-aroused or non-erect state, the arteries servingthe corpus cavernosum are maintained in a relatively constricted state,thereby limiting the blood flow to the corpus cavernosum. In the arousedstate, the smooth muscles associated with the arteries relax and bloodflow to the corpus cavernosum greatly increases, causing expansion andrigidity of the penis. Smooth muscle contraction opens valves throughwhich blood can flow from the corpus cavernosum into the extracavernosalveins. When the relevant smooth muscles relax, the valves closediminishing venous outflow from the corpus cavernosum. When accompaniedby increased arterial blood flow into the corpus cavernosum, thisresults in engorgement of the corpus cavernosum and an erection.

The pre-orgasmic sexual response in females can be broken down intodistinct phases. Both the excitement phase and the plateau phase involvevasodilation and engorgement (vasocongestion) of the genitalia witharterial blood in a manner analogous to the male erectile response.

The excitement phase of the female sexual response is characterized byvasocongestion in the walls of the vagina which leads to thetransudation of vaginal fluids and vaginal lubrication. Further, theinner one-third of the vaginal barrel expands and the cervix and thebody of the uterus become elevated. This is accompanied by theflattening and elevation of the labia majora and an increase in clitoralsize.

The plateau phase follows the excitement phase in the female sexualresponse and is characterized by prominent vasocongestion in the outerone-third of the vagina, causing a narrowing of the opening of thevagina and a retraction of the shaft and the glans of the clitorisagainst the symphysis pubis. These responses are also accompanied by amarked vasocongestion of the labia.

The vasocongestive aspects of the female sexual response are notrestricted to the genitalia in that areolar engorgement also occurs,sometimes to the extent that it masks the antecedent nipple erectionthat usually accompanies the excitement phase.

The vasodilation and vasocongestive responses may also be induced bypharmacological action without psychological stimulation or arousal bythe female. Similarly, the male sexual response may also be induced bypharmacological action without psychological stimulation or arousal.

The present invention is directed to the treatment and/or prevention ofsexual dysfunctions in animals, including males and females, byadministering the compounds and compositions described herein. Thepresent invention is also directed to improving and/or enhancing thesexual response in animals, including males and females, byadministering the compounds and/or compositions described herein. Thenovel compounds and novel compositions of the present invention aredescribed in more detail below.

Contemplated PDE inhibitors for use in the present invention include,for example, dipyridamole, zaprinast, sildenafil, filaminast,denbufyllene, piclamilast, zardaverine, rolipram and the like.

Sources of information for the above include Goodman and Gilman, ThePharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc.(1996), The Physician's Desk Reference (49th Ed.), Medical Economics(1995), Drug Facts and Comparisons (1993 Ed), Facts and Comparisons(1993), and The Merck Index (12th Ed.), Merck & Co., Inc. (1996), thedisclosures of each of which are incorporated herein by reference intheir entirety.

A principal aspect of the invention relates to novel nitrosated and/ornitrosylated phosphodiesterase inhibitors.

One embodiment of the invention provides compounds having structure I:

wherein R₁ is an alkoxy, a cycloalkoxy, a halogen, or

R₂ is a hydrogen, an alkoxy, or a haloalkcoxy; and

R₃ is:

 wherein

D is (i) —NO, (ii) —NO₂, (iii)—C(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q, wherein R_(d) is ahydrogen, a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or aheteroaryl; Y is oxygen, sulfur, carbon or NR_(i), wherein R_(i) is ahydrogen or a lower alkyl; R_(e) and R_(f) are each independently ahydrogen, a lower alkyl, a haloalkyl, an alkoxy, a cycloalkyl, an aryl,a heteroaryl, an arylalkyl, an amino, an alkylamino, an amido, analkylamido, a dialkylamino, a carboxylic acid, a carboxylic ester, acarboxamido or —T—Q, or R_(e) and R_(f) taken together are a carbonyl, acycloalkyl, a heterocyclic ring or a bridged cycloalkyl; p is an integerfrom 1 to 10; T is independently a covalent bond, oxygen, sulfur ornitrogen; Z is a covalent bond, a lower alkyl, a haloalkyl, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, anarylheterocyclic ring or (C(R_(e))(R_(f)))_(p); and Q is —NO or —NO₂;(iv) —C(O)—Y—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p) wherein G is a covalentbond, —T—C(O)—, —C(O)—T— or T, wherein q is an integer from 0 to 5, andY, Z, R_(e), R_(f), p, T and Q are as defined above; or (v)—P—Z—(G—(C(R_(e))(R_(f)))_(q)—T—Q)_(p), wherein P is a carbonyl, aphosphoryl or a silyl, and Z, G, p, q, T, Q, R_(e) and R_(f) are asdefined above;

R₄ is (i) hydrogen, (ii) —C(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q,(iii)—C(O)—T—(C(R_(e))(R_(f)))_(p)—T—Q, or (iv)—C(O)—Z—(G—(C(R_(e))(R_(f)))_(p)—T—Q)_(p); and wherein R_(d) & R_(e)R_(f), p, G, T, Q, Y, and Z are defined above;

R₅ is a lone pair of electrons or—C(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q wherein R_(d), R_(e),R_(f), p, T, Q, Y, and Z are defined above;

R₁₁ and R₁₂ are independently selected from hydrogen or R₄, wherein R₄is as defined above with the proviso that R₁₁ and R₁₂ are not bothhydrogen;

X is a halogen, and D₁ is D or hydrogen, wherein D is as defined above.

Another embodiment of the invention provides compounds having structureII:

wherein R₄ is defined above;

R₈ is a hydrogen or a lower alkyl;

R₉ is a hydrogen or a halogen; and

R₁₀ is:

(i) hydrogen,

 wherein R₈ is as defined above.

Another embodiment of the invention provides compounds having structureIII:

wherein,

E is nitrogen or—CH—;

G is nitrogen or —C(R₈)—;

R₂₁ is:

R₂₂ is R₁₂ or a lower alkyl; and

R₈, R₁₁, and R₁₂ are as defined above.

Another embodiment of the invention provides compounds having structureIV:

wherein,

F is —CH₂— or sulfur;

R₄ and R₈ are as defined above; and

R₁₃ is:

wherein,

R₆ and R₇ are independently hydrogen or R₄, wherein R₄ is as definedabove.

Another embodiment of the invention provides compounds having structureV:

wherein,

R₄ is defined above; and

R₁₄ is:

wherein R₆ is as defined above.

Another embodiment of the invention provides compounds having structureVI:

wherein,

R₁₅ is a hydrogen, a lower alkyl, R₄, or —(CH₂)₄—C(CH₃)₂—O—D₁;

R₁₆ is a lower alkyl; and

R₁₇ is a hydrogen, a lower alkyl, CH₃—C(O)—CH₂—; CH₃—O—CH₂—; or D withthe proviso that either R₁₅ or R₁₇ must be selected to contain D,wherein D and D₁ are as defined above.

Another embodiment of the invention provides compounds having structureVII:

wherein,

R₄ and R₈ are as defined above; and

R₁₈ is:

and wherein R₈ is as defined above.

Another embodiment of the invention provides compounds having structureVIII:

wherein,

R₁₉ is:

and wherein R₄, R₁₁, and R₁₂ are defined above.

Another embodiment of the invention provides compounds having structureIX:

wherein,

R₂₀ is:

and wherein R₄ is defined above.

Another embodiment of the invention provides compounds having structureX:

wherein,

a is an integer from 2 to 3 and D and D₁ are defined above.

Compounds of the invention which have one or more asymmetric carbonatoms may exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. It is to be understood that the present invention anticipatesand includes within its scope all such isomers and mixtures thereof.

Another aspect of the invention provides processes for making the novelcompounds of the invention and to the intermediates useful in suchprocesses. Some of the compounds of the invention are synthesized asshown in FIGS. 1-30, in which R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R16, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R_(e),R_(f), a, p, D, D₁, E, F, G, and X are as defined above or as depictedin the reaction schemes for structures I-X; p₁ is an oxygen protectinggroup and p² is a sulfur protecting group. The reactions are performedin solvents appropriate to the reagents, and materials used are suitablefor the transformations being effected. It will be understood by oneskilled in the art of organic synthesis that the functionality presentin the molecule must be consistent with the chemical transformationproposed. This will, on occasion, necessitate judgment by the routine asto the order of synthetic steps, protecting groups required, anddeprotection conditions. Substituents on the starting materials may beincompatible with some of the reaction conditions required in some ofthe methods described, but alternative methods and substituentscompatible with the reaction conditions will be readily apparent to theskilled practitioner in the art. The use of sulfur and oxygen protectinggroups is well known in the art for protecting thiol and alcohol groupsagainst undesirable reactions during a synthetic procedure and many suchprotecting groups are known, as described, for example, by T. H. Greeneand P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley &Sons, New York (1991), the disclosure of which is incorporated byreference herein in its entirety.

Another embodiment of this aspect provides processes for makingcompounds having structure I and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (I) wherein R1, R₂, R_(e), R_(f), and p aredefined above and a nitrite containing imide is representative of the R₃group as defined herein may be prepared as outlined in FIG. 1. The amidegroup of formula 1 is converted to the imide of formula 2 wherein p,R_(e) and R_(f) are defined above by reaction with an appropriateprotected alcohol containing activated acylating agent wherein P¹ is asdefined above. Preferred methods for the formation of imides arereacting the amide with the preformed acid chloride of the protectedalcohol containing acid in the presence of pyridine at low temperatureor condensing the amide and protected alcohol containing symmetricalanhydride in the presence of a catalyst such as sulfuric acid. Preferredprotecting groups for the alcohol moiety are silyl ethers such as atrimethylsilyl ether, a tert-butyldimethylsilyl ether, or atert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction with a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite, ornitrosonium tetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIA.

Nitroso compounds of formula (I) wherein R₁, R₂, R_(e), R_(f), and p aredefined above and a nitrosothiol containing imide is representative ofthe R₃ group as defined herein may be prepared as outlined in FIG. 2.The amide group of formula 1 is converted to the imide of formula 3wherein p, R_(e) and R_(f) are defined herein by reaction with anappropriate protected thiol containing activated acylating agent whereinp² is as defined herein. Preferred methods for the formation of imidesare reacting the amide with the preformed acid chloride of the protectedthiol containing acid in the presence of pyridine at low temperature orcondensing the amide and protected thiol containing symmetricalanhydride in the presence of a catalyst such as suifriric acid.Preferred protecting groups for the thiol moiety are as a thioester suchas a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamatesuch as N-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zincin dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically used to hydrolyze thioesters andNmethoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thi oether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of the formula IB. Alternatively, treatment of thedeprotected thiol derived from compound 3 with a stoichiometric quantityof sodium nitrite in an acidic aqueous or alcoholic solution affords thecompound of the formula IB.

Nitro compounds of formula (1) wherein R₁, R₂, R_(e), R_(f), and p aredefined herein and a nitrate containing imide is representative of theR₃ group as defined herein may be prepared as outlined in FIG. 3. Theamide group of the formula 1 is converted to the imide of the formula 4wherein p, R_(e) and R_(f) are defined above and X is a halogen byreaction with an appropriate halide containing activated acylatingagent. Preferred methods for the formation of imides are reacting theamide with the preformed acid chloride of the halide containing acid inthe presence of pyridine at low temperature or condensing the amide andhalide containing symmetrical anhydride in the presence of a catalystsuch as suifriric acid. Prefrrred halides are bromide and iodide.Reaction of the imide of the formula 4 with a suitable penetrating agentsuch as silver nitrate in an inert solvent such as acetonitrile affordsthe compound of the formula IC.

Another embodiment of this aspect provides processes for makingcompounds having structure II and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (II) wherein R, R₉, R₁₀, R_(e), R_(f), andp are defined above and a nitrite containing amide is representative ofthe R₄ group as defined above may be prepared as outlined in FIG. 4. Theimidazo[2,1-b]quinazoline of formula 5 is converted to theacylimidazo[2,1-b]quinazoline of formula 6 wherein p, R_(e) and R_(f)are defined above by reaction with an appropriate protected alcoholcontaining activated acylating agent wherein P¹ is as defined above.Preferred methods for the formation of acylimidazo[2,1-b]quinazolinesare reacting the imidazo[2,1-b]quinazoline with the preformed acidchloride or symmetrical anhydride of the protected alcohol containingacid or condensing the imidazo[2,1-b]quinazoline and protected alcoholcontaining acid in the presence of a dehydrating agent such asdicyclohexylcarbodiimide (DCC) or 1-ethyl-3 (3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC HCl) with or without a catalyst such as4-dimethylamino-pyridine (DMAP) or 1-hydroxybenzotriazole (HOBt).Preferred protecting groups for the alcohol moiety are silyl ethers suchas a trimethylsilyl or tertbutyldimethylsilyl ether. Deprotection of thehydroxyl moiety (fluoride ion is the preferred method for removing silylether protecting groups) followed by reaction a suitable nitrosylatingagent such as thionyl chloride nitrite, thionyl dinitrite, ornitrosonium tetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIA.

Nitroso compounds of formula (II) wherein R₈, R₉, R₁₀, R_(e), R_(f), andp are defined above and a nitrosothiol containing amide isrepresentative of the R₄ group as defined above on may be prepared asoutlined in FIG. 5. The imidazo[2,1-b] quinazoline of formula 5 isconverted to the acylimidazo[2,1-b]quinazoline of formula 7 wherein p,R_(e) and R_(f) are defined above by reaction with an appropriateprotected thiol containing activated acylating agent wherein P is asdefined above. Preferred methods for the formation of acylaiedimidazo[2,1-b]quinazolines are reacting the imidazo[2,1-b]quinazolinewith the preformed acid chloride or symmetrical anhydride of theprotected thiol containing acid or condensing theimidazo[2,1-b]quinazoline and protected thiol containing acid in thepresence of a dehydrating agent such as DCC or EDAC HCl with or withouta catalyst such as DMAP or HOBt. Preferred protecting groups for thethiol moiety are as a thioester such as a thioacetate or thiobenzoate,as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenyiphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IIB.Alternatively, treatment of the deprotected thiol derived from compound7 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of the formula IIB.

Nitro compounds of formula (II) wherein R₈, R₉, R₁₀, R_(e), R_(f), and pare defined above and a nitrate containing amide is representative ofthe R₄ group as defined above may be prepared as outlined in FIG. 6. Theimidazo[2,1-b]quinazoline of formula 5 is converted to theacylimidazo[2,1-b]quinazoline of formula 8 wherein p, R_(e) and R_(f)are defined above and X is a halogen by reaction with an appropriatehalide containing activated acylating agent. Preferred methods for theformation of the acylimidazo[2,1-b]quinazolines are reacting theimidazo[2,1-b]quinazoline with the preformed acid chloride orsymmetrical anhydride of the halide containing acid or condensing thealcohol and halide containing acid in the presence of a dehydratingagent such as DCC or EDAC HCl with or without a catalyst such as DMAP orHOBt. Preferred halides are bromide and iodide. Reaction of theacylimidazo[2,1-b]quinazoline of the formula 8 with a suitable nitratingagent such as silver nitrate in an inert solvent such as acetonitrileaffords the compound of the formula IIC.

Another embodiment of this aspect provides processes for makingcompounds having structure III and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (III) wherein E, G, R₂₁, R₂₂, R_(e), R_(f),and p are defined above and a nitrite containing amide is representativeof the R₁₁ group as defined in this specification may be prepared asoutlined in FIG. 7. The purine-6-one group of formula 9 is converted tothe acylated purine-6-one of formula 10 wherein p, R_(e) and R_(f) aredefined above by reaction with an appropriate protected alcoholcontaining activated acylating agent wherein P¹ is as defined in thisspecification. Preferred methods for the formation of acylatedpurine-6-ones are reacting the purine-6-one with the preformed acidchloride or symmetrical anhydride of the protected alcohol containingacid. Preferred protecting groups for the alcohol moiety are silylethers such as a tert-butyldimethylsilyl ether or atert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl di nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIIIA.

Nitroso compounds of formula (III) wherein E, G, R₂₁, R₂₂, R_(e), R_(f),and p are defined above and an nitrosothiol containing amide isrepresentative of the R₁₁ group as defined above may be prepared asoutlined in FIG. 8. The purine-6-one group of formula 9 is converted tothe acylated purine-6-one of formula 11 wherein p, R_(e) and R_(f) aredefined above by reaction with an appropriate protected thiol containingactivated acylating agent wherein P² is as defined above. Preferredmethods for the formation of acylated purine-6-ones are reacting thepurine-6-one with the preformed acid chloride or symmetrical anhydrideof the protected alcohol containing acid. Preferred protecting groupsfor the thiol moiety are as a thioester such as a thioacetate orthiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethylthiocarbamate, or as a thioether such as a paramethoxybenzyl thioether,a tetrahydropyranyl thioether or a 2,4,6-trimethoxyberzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IIIB.Alternatively, treatment of the deprotected thiol derived from compound11 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of the formula IIIB.

Nitro compounds of formula (III) wherein E, G, R₂₁, R₂₂, R_(e), R_(f),and p are defined above and an nitrate containing amide isrepresentative of the R11 group as defined above may be prepared asoutlined in FIG. 9. The purine-6-one of formula 9 is converted to theacylated purine-6-one of formula 12 wherein p, R_(e) and R_(f) aredefined above and X is halogen. Preferred methods for the formation ofacylated purine-6-ones are reacting the purine-6-one with the preformedacid chloride or symmetrical anhydride of the halide containing acid.Preferred halides are bromide and iodide. Reaction of the of theacylated purine-6-one of the formula 12 with a suitable nitrating agentsuch as silver nitrate in an inert solvent such as acetonitrile affordsthe compound of the formula IIIC.

Another embodiment of this aspect provides processes for makingcompounds having structure IV and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (IV) wherein F, R₈ R₁₃, R_(e), R_(f), and pare defined above and a nitrite containing acyl hydrazide isrepresentative of the R₄ group as defined above may be prepared asoutlined in FIG. 10. The 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazineof formula 13 is converted to the 3 (2-acyl)-pyridazinone or2-acyl-1,2,3,4-thiadiazine of formula 14 wherein p, R_(e) and R_(f) aredefined above by reaction with an appropriate protected alcoholcontaining activated acylating agent wherein P¹ is defined above.Preferred methods for the formation of 3 (2-acyl)-pyridazinone or2-acyl-1,2,3,4-thiadiazine are reacting the 3 (2H)-pyridazinone or2H-1,2,3,4-thiadiazine with the preformed acid chloride or symmetricalanhydride of the protected alcohol containing acid or condensing the 3(2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine and protected alcoholcontaining acid in the presence of a dehydrating agent such as DCC orEDAC HCl with a catalyst such as DMAP or HOBt. Preferred protectinggroups for the alcohol moiety are silyl ethers such as atert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactiona suitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite, or nitrosonium tetrafluoroborate in a suitable anhydroussolvent such as dichloromethane, THF, DMF, or acetonitrile with orwithout an amine base such as pyridine or triethylamine affords thecompound of the formula IVA.

Nitroso compounds of formula (IV) wherein F, R₈, R₁₃, R_(e), R_(f), andp are defined above and a nitrosothiol containing acyl hydrazide isrepresentative of the R₄ group as defined above may be prepared asoutlined in FIG. 11. The 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazineof formula 13 is converted to the 3 (2-acyl)-pyridazinone or2-acyl-1,2,3,4-thiadiazine of formula 15 wherein p, R_(e) and R_(f) aredefined above by reaction with an appropriate protected thiol containingactivated acylating agent wherein P² is as defined above. Preferredmethods for the formation of 3 (2-acyl)-pyridazinones or2-acyl-1,2,3,4-thiadiazines are reacting the 3 (2-H)-pyridazinone or2H-1,2,3,4-thiadiazine with the preformed acid chloride or symmetricalanhydride of the protected thiol containing acid or condensing the 3(2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine and protected thiolcontaining acid in the presence of a dehydrating agent such as DCC orEDAC HCl with a catalyst such as DMAP or HOBt. Preferred protectinggroups for the thiol moiety are as a thioester such as a thioacetate orthiobenzoate, as a disulfide, or as a thioether such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zincin dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whilemercuric trifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula IVB.Alternatively, treatment of the deprotected thiol derived from compound15 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of the formula IVB.

Nitro compounds of formula (IV) wherein F, R₈ R₁₃, R_(e), R_(f), and pare defined above and an nitrate containing acyl hydrazide isrepresentative of the R₄ group as defined above may be prepared asoutlined in FIG. 12. The 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazineof formula 13 is converted to the 3 (2-acyl)-pyridazinone or2-acyl-1,2,3,4-thiadiazine of formula 16 wherein p, R_(e) and R_(f) aredefined above and X is halogen. Preferred methods for the formation of 3(2-acyl)-pyridazinones or 2-acyl-1,2,3,4-thiadiazines are reacting the 3(2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine with the preformed acidchloride or symmetrical anhydride of the halide containing acid orcondensing the 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine and halidecontaining acid in the presence of a dehydrating agent such as DCC orEDAC HCl with a catalyst such as DMAP or HOBt. Preferred halides arebromide and iodide. Reaction of the 3 (2-acyl)-pyridazinone or2-acyl-1,2,3,4-thiadiazine of formula 16 with a suitable nitrating agentsuch as silver nitrate in an inert solvent such as acetonitrile affordsthe compound of the formula IVC.

Another embodiment of this aspect provides processes for makingcompounds having structure V and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (V) wherein R₁₄, R_(e), R_(f), and p aredefined above and an nitrite containing imide is representative of theR₄ group as defined above may be prepared as outlined in FIG. 13. Theamide group of formula 17 is converted to the imide of formula 18wherein p, R_(e), and R_(f) are defined as in this specification byreaction with an appropriate protected alcohol containing activatedacylating agent wherein P¹ is as defined in this specification.Preferred methods for the formation of imides are reacting the amidewith the preformed acid chloride of the protected alcohol containingacid in the presence of pyridine at low temperature or condensing theamide and protected alcohol containing symmetrical anhydride in thepresence of a catalyst such as sulfuric acid. Preferred protectinggroups for the alcohol moiety are silyl ethers such as atert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactiona suitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite, or nitrosonium tetrafluoroborate in a suitable anhydroussolvent such as dichloromethane, THF, DMF, or acetonitrile with orwithout an amine base such as pyridine or triethylamine affords thecompound of the formula VA.

Nitroso compounds of formula (V) wherein R₁₄, R_(e), R_(f), and p aredefined above and a nitrosothiol containing imide is representative ofthe R₄ group as defined above may be prepared as outlined in FIG. 14.The amide group of formula 17 is converted to the imide of formula 19wherein p, R_(e) and R_(f) are defined above by reaction with anappropriate protected thiol containing activated acylating agent whereinP² is as defined above. Preferred methods for the formation of imidesare reacting the amide with the preformed acid chloride of the protectedthiol containing acid in the presence of pyridine at low temperature orcondensing the amide and protected thiol containing symmetricalanhydride in the presence of a catalyst such as sulfuric acid. Preferredprotecting groups for the thiol moiety are as a thioester such as athioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such asN-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zincin dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically used to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of the formula VB. Alternatively, treatment of thedeprotected thiol derived from compound 19 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of the formula VB.

Nitro compounds of formula (V) wherein R₁₄, R_(e), R_(f), and p aredefined above and a nitrate containing imide is representative of the R₄group as defined above may be prepared as outlined in FIG. 15. The amidegroup of the formula 17 is converted to the imide of the formula 20wherein p, R_(e) and R_(f) are defined above and X is a halogen byreaction with an appropriate halide containing activated acylatingagent. Preferred methods for the formation of imides are reacting theamide with the preformed acid chloride of the halide containing acid inthe presence of pyridine at low temperature or condensing the amide andhalide containing symmetrical anhvdride in the presence of a catalystsuch as sulfuric acid. Preferred halides are bromide and iodide.Reaction of the imide of the formula 20 with a suitable nitrating agentsuch as silver nitrate in an inert solvent such as acetonitrile affordsthe compound of the formula VC.

Another embodiment of this aspect provides processes for makingcompounds having structure VI and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (VI) wherein R₁₅, R₁₆, R_(e), R_(f) and pare defined above and a nitrite containing acyl imidazolide isrepresentative of the R₁₇ group as defined above may be prepared asoutlined in FIG. 16. The 1H-purine-2,6-dione of formula 21 is convertedto the acylated derivative of the formula 22 wherein p, R_(e) and R_(f)are defined above by reaction with an appropriate protected alcoholcontaining activated acylating agent wherein P¹ is defined above.Preferred methods for the formation of acylated 1H-purine-2,6-diones arereacting the 1H-purine-2,6-dione with the preformed acid chloride orsymmetrical anhydride of the protected alcohol containing acid orcondensing the 1H-purine-2,6-dione and protected alcohol containing acidin the presence of a dehydrating agent such as DCC or EDAC HCl with acatalyst such as DMAP or HOBt. Preferred protecting groups for thealcohol moiety are silyl ethers such as a tert-butyldimethylsilyl etheror a tert-butyldimethyl-silyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitroslating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaVIA.

Nitroso compounds of formula (VI) wherein R₁₅, R₁₆, R_(e), R_(f), and pare defined above and a nitrosothiol containing acyl imidazolide isrepresentative of the R₁₇ group as defined above may be prepared asoutlined in FIG. 17. The 1H-purine-2,6-dione of formula 21 is convertedto the acylated derivative of the formula 23 wherein p, R_(e) and R_(f)are defined above by reaction with an appropriate protected thiolcontaining activated acylating agent wherein P² is defined above.Preferred methods for the formation of acylated 1H-purine-2,6-diones arereacting the 1H-purine-2,6-dione with the preformed acid chloride orsymmetrical anhydride of the protected thiol containing acid orcondensing the 1H-purine-2,6-dione and protected thiol containing acidin the presence of a dehydrating agent such as DCC or EDAC HCl with acatalyst such as DMAP or HOBt. Preferred protecting groups for the thiolmoiety are as a thioester such as a thioacetate or thiobenzoate, as adisulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, oras a thioether such as a paramethoxy-benzyl thioether, atetrahydropyranyl thioether or a 2,4,6-trimethoxybenzyl thioether.Deprotection of the thiol moiety (zinc in dilute aqueous acid,triphenylphosphine in water and sodium borohydride are preferred methodsfor reducing disulfide groups while aqueous base is typically utilizedto hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate, silver nitrate, or strong acids such astrifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxybenzyl thioether, a tetrahydropyranyl thioether, or a2,4,6-trimethoxybenzyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionvl dinitrite,a lower alkyl nitrite such as tert-butyl nitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such as methylenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethylamine affords the compound of the formula VIB.Alternatively, treatment of the deprotected thiol derived from compound23 with a stoichiometric quantity of sodium nitrite in an acidic aqueousor alcoholic solution affords the compound of the formula VIB.

Nitro compounds of formula (VI) wherein R₁₅, R₁₆, R_(e), R_(f), and pare defined above and an O-nitrosated acylated 1H-purine-2,6-dione isrepresentative of the R₁₇ group as defined above may be prepared asoutlined in FIG. 18. The 1H-purine-2,6-dione of the formula 21 isconverted to the acylated derivative of the formula 24 wherein p, R_(e)and R_(f) are defined above and X is a halogen by reaction with anappropriate halide containing activated acylating agent. Preferredmethods for the formation of acylated 1H-purine-2,6-diones are reactingthe 1H-purine-2,6-dione with the preformed acid chloride or symmetricalanhydride of the halide containing acid or condensing the1H-purine-2,6-dione and halide containing acid in the presence of adehydrating agent such as DCC or EDAC HCl with a catalyst such as DMAPor HOBt. Preferred halides are bromide and iodide. Reaction of theacylated 1H-purine-2,6-dione of the formula 24 with a suitable nitratingagent such as silver nitrate in an inert solvent such as acetonitrileaffords the compound of formula VIC.

Another embodiment of this aspect provides processes for makingcompounds having structure VII and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (VII) wherein R₈, R₁₈, R_(e), R_(f), and pare defined above and a nitrite containing imide is representative ofthe R₄ group as defined above may be prepared as outlined in FIG. 19.The amide nitrogen of formula 25 is converted to the imide of formula 26wherein p, R_(e) and R_(f) are defined above by reaction with anappropriate protected alcohol containing activated acylating agentwherein P¹ is defined above. Preferred methods for the formation ofimides are reactin, the amide with the preformed acid chloride of theprotected alcohol containing acid in the presence of pyridine at lowtemperature or condensing the amide and protected alcohol containingsymmetrical anhydride in the presence of a catalvst such as sulfuricacid. Preferred protecting groups for the alcohol moiety are silylethers such as a tert-butyldimethylsilyl ether or atertbutyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaVIIA.

Nitroso compounds of formula (VII) wherein R₈, R₁₈, R_(e), R_(f), and pare defined above and a nitrosothiol containing imide is representativeof the R₄ group as defined above may be prepared as outlined in FIG. 20.The amide nitrogen of formula 25 is converted to the imide of formula 27wherein p, R_(e) and R_(f) are defined above by reaction with anappropnate protected thiol containing activated acylating agent whereinP² is defined above. Preferred methods for the formation of imides arereacting the amide with the preformed acid chloride of the protectedthiol containing acid in the presence of pyridine at low temperature orcondensing the amide and protected thiol containing symmetricalanhydride in the presence of a catalyst such as sulfuric acid. Preferredprotecting groups for the thiol moiety are as a thioester such as athioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such asN-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety (zincin dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disultide groups whileaqueous base is typically used to hydrolyze thioesters andNmethoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyt thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of the formula VIIB. Alternatively, treatment of thedeprotected thiol derived from compound 27 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of the formula VIIB.

Nitro compounds of formula (VII) wherein R₈, R₁₈, R_(e), R_(f), and pare defined above and a nitrate containing imide is representative ofthe R₄ group as defined above may be prepared as outlined in FIG. 21.The amide group of the formula 25 is converted to the imide of theformula 28 wherein p, R_(e) and R_(f) are defined above and X is ahalogen by reaction with an appropriate halide containing activatedacylating agent. Preferred methods for the formation of imides arereacting the amide with the preformed acid chloride of the halidecontaining acid in the presence of pyridine at low temperature orcondensing the amide and halide containing symmetrical anhydride in thepresence of a catalyst such as sulfuric acid. Preferred halides arebromide and iodide. Reaction of the imide of the formula 28 with asuitable nitrating agent such as silver nitrate in an inert solvent suchas acetonitrile affords the compound of the formula VIIC.

Another embodiment of this aspect provides processes for makingcompounds having structure VIII and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (VIII) wherein R_(e) R_(f), and p aredefined above and a nitrite containing imide is representative of theR₁₉ group as defined above may be prepared as outlined in FIG. 22. Theamide nitrogen of formula 29 is converted to the imide of formula 30wherein p, R_(e) and R, are defined above by reaction with anappropriate protected alcohol containing activated acylating agentwherein P¹ is defined above. Preferred methods for the formation ofimides are reacting the amide with the preformed acid chloride of theprotected alcohol containing acid in the presence of pyridine at lowtemperature or condensing the amide and protected alcohol containingsymmetrical anhydride in the presence of a catalyst such as suiftiricacid. Preferred protecting groups for the alcohol moiety are silylethers such as a tert-butyldimethylsilyl ether or atert-butyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoroborate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or tri ethyl amine affords the compound of the formulaVIIIA.

Nitroso compounds of formula (VIII) wherein R_(e), R_(f), and p aredefined above and a nitrosothiol containing imide is representative ofthe R₁₉ group as defined above may be prepared as outlined in FIG. 23.The amide nitrogen of formula 29 is converted to the imide of formula 31wherein p, R_(e) and R_(f) are defined above by reaction with anappropriate protected thiol containing activated acylating agent whereinP² is defined above. Preferred methods for the formation of imides arereacting, the amide with the preformed acid chloride of the protectedthiol containing acid in the presence of pyridine at low temperature orcondensing the amide and protected alcohol containing symmetricalanhvdride in the presence of a catalyst such as sulfuric acid. Preferredprotecting groups for the thiol moiety are as a thioester such as athioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such asN-methoxymethyl thiocarbamate, or as a thioether such as aparamethoxybenzyl thioether, a tetrahydropyranyl thioether or a2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety,(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing di sulfide groups whileaqueous base is typically utilized to hydrolyze thioesters andNmethoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl di nitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of the formula VIIB. Alternatively, treatment of thedeprotected thiol derived from compound 31 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compound of the formula VIIIB.

Nitro compounds of formula (VIII) wherein R_(e) R_(f), and p are definedabove and a nitrate containing imide is representative of the R₁₉ groupas defined above may be prepared as outlined in FIG. 24. The amide groupof the formula 29 is converted to the imide of the formula 32 wherein p,R_(e) and R_(f) are defined above and X is a halogen by reaction with anappropriate halide containing activated acylating agent. Preferredmethods for the formation of imides are reacting the amide with thepreformed acid chloride of the halide containing acid in the presence ofpyridine at low temperature or condensing the amide and halidecontaining symmetrical anhydride in the presence of a catalyst such assulfuric acid. Preferred halides are bromide and iodide. Reaction of theimide of the formula 32 with a suitable nitrating agent such as silvernitrate in an inert solvent such as acetonitrile affords the compound ofthe formula VIIIC.

Another embodiment of this aspect provides processes for makingcompounds having structure IX and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (IX) wherein R₂₀, R_(e), R_(f), and p aredefined above and an nitrate containing imide or sulfonimide isrepresentative of the R₄ group as defined above may be prepared asoutlined in FIG. 25. The amide or sulfonamide nitrogen of formula 33 isconverted to the imide or sulfonimide of formula 34 wherein p, R_(e) andR_(f) are defined above by reaction with an appropriate protectedalcohol containing activated acylating agent wherein P¹ is definedabove. Preferred methods for the formation of imides or sulfonimides arereacting the amide or sulfonimide with the preformed acid chloride ofthe protected alcohol containing acid in the presence of pyridine at lowtemperature or condensing the amide or sulfonimide and protected alcoholcontaining symmetrical anhydride in the presence of a catalyst such assulfuric acid. Preferred protecting groupsfor the alcohol moiety aresilyl ethers such as a tert-butyldimethylsilyl ether or atertbutyldiphenylsilyl ether. Deprotection of the hydroxyl moiety(fluoride ion is the preferred method for removing silyl etherprotecting groups) followed by reaction a suitable nitrosylating agentsuch as thionyl chloride nitrite, thionyl dinitrite, or nitrosoniumtetrafluoro-borate in a suitable anhydrous solvent such asdichloromethane, THF, DMF, or acetonitrile with or without an amine basesuch as pyridine or triethylamine affords the compound of the formulaIXA.

Nitroso compounds of formula (IX) wherein R₂₀, R_(e), R_(f) and p aredefined above and an nitrosothiol containing imide or sulfonimide isrepresentative of the R₄ group as defined above may be prepared asoutlined in FIG. 26. The amide or sulfonamide nitrogen of formula 33 isconverted to the imide or sulfonimide of formula 35 wherein p, R_(e) andR_(f) are defined above by reaction with an appropriate protected thiolcontaining activated acylating agent wherein P² is defined above.Preferred methods for the formation of imides or sulfonimides arereacting the amide or sulfonimide with the preformed acid chloride ofthe protected thiol containing acid in the presence of pyridine at lowtemperature or condensing the amide or sulfonimide and protected thiolcontaining symmetrical anhydride in the presence of a catalyst such assulfuric acid. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioethersuch as a paramethoxy-benzyl thioether, a tetrahydropyranyl thioether ora 2,4,6-trimethoxybenzyl thioether. Deprotection of the thiol moiety(zinc in dilute aqueous acid, triphenylphosphine in water and sodiumborohydride are preferred methods for reducing disulfide groups whileaqueous base is typically utilized to hydrolyze thioesters andN-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silvernitrate, or strong acids such as trifluoroacetic or hydrochloric acidand heat are used to remove a paramethoxybenzyl thioether, atetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl thioethergroup) followed by reaction a suitable nitrosylating agent such asthionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite suchas tert-butyl nitrite, or nitrosonium tetrafluoroborate in a suitableanhydrous solvent such as methylene chloride, THF, DMF, or acetonitrilewith or without an amine base such as pyridine or triethylamine affordsthe compound of the formula IXB. Alternatively, treatment of thedeprotected thiol derived from compound 35 with a stoichiometricquantity of sodium nitrite in an acidic aqueous or alcoholic solutionaffords the compcund of the formula IXB.

Nitro compounds of formula (IX) wherein R₂₀, R_(e) R_(f), and p aredefined above and a nitrate containing imide or sulfonimide isrepresentative of the R₄ group as defined above may be prepared asoutlined in FIG. 27. The amide or sulfonamide group of the formula 33 isconverted to the imide or sulfonimide of the formula 36 wherein p, R_(e)and R_(f) are defined above and X is a halogen by reaction with anappropriate halide containing activated acylating agent. Preferredmethods for the formation of imides or sulfonimides are reacting theamide or sulfonamide with the preformed acid chloride of the halidecontaining acid in the presence of pyridine at low temperature orcondensing the amide or sulfonamide and halide containing symmetricalanhydride in the presence of a catalyst such as sulfuric acid. Preferredhalides are bromide and iodide. Reaction of the imide or sulfonimide ofthe formula 36 with a suitable nitrating agent such as silver nitrate inan inert solvent such as acetonitrile affords the compound of theformula IXC.

Another embodiment of this aspect provides processes for makingcompounds having structure X and to the intermediates useful in suchprocesses as follows.

Nitroso compounds of formula (X) wherein D₁, R_(e), R_(f), and p aredefined above and a nitrite containing ester is representative of the Dgroup as defined above may be prepared according to FIG. 28. The alcoholgroup of formula 37 is converted to the ester of formula 38 wherein p,R_(e) and R are defined above by reaction with an appropriate protectedalcohol containing activated acylating agent wherein P¹ is as defined inthis specification. Preferred methods for the formation of esters arereacting the alcohol with the preformed acid chloride or symmetricalanhydride of the protected alcohol containing acid or condensing thealcohol and protected alcohol containing acid with a dehydrating agentsuch as DCC or EDAC HCl in the presence of a catalyst such as DMAP orHOBt. Preferred protecting groups for the alcohol moiety are silylethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.Deprotection of the hydroxyl moiety (fluoride ion is the preferredmethod for removing silyl ether protecting groups) followed by reactiona suitable nitrosylating agent such as thionyl chloride nitrite, thionyldinitrite, or nitrosonium tetrafluoro-borate in a suitable anhydroussolvent such as dichloromethane, THF, DMF, or acetonitrile with orwithout an amine base such as pyridine or triethylamine affords thecompound of the formula XA.

Nitroso compounds of formula (X) wherein D₁, R_(e) R_(f), and p aredefined above and a nitrosothiol containing ester is representative ofthe D group as defined above may be prepared according to FIG. 29. Thealcohol group of the formula 37 is converted to the ester of the formula39 wherein p, R_(e) and R_(f) are defined above by reaction with anappropriate protected thiol containing activated acylating agent whereinP² is defined above. Preferred methods for the formation of esters arereacting the alcohol with the preformed acid chloride or symmetricalanhydride of the protected thiol containing acid or condensing thealcohol and protected thiol containing acid with a dehydrating agentsuch as DCC or EDAC HCl in the presence of a catalyst such as DMAP orHOBt. Preferred protecting groups for the thiol moiety are as athioester such as a thioacetate or thiobenzoate, as a disulfide, as athiocarbamate such as N-methoxymethyl thiocarbamate, or as a thiethersuch as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether ora S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc indilute aqueous acid, triphenyl-phosphine in water and sodium borohydrideare preferred methods for reducing disulfide groups while aqueous baseis typically utilized to hydrolyze thioesters and N-methoxymethylthiocarbamates and mercuric trifluoroacetate, silver nitrate, or strongacids such as trifluoroacetic or hydrochloric acid and heat are used toremove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or aS-triphenylmethyl thioether group) followed by reaction a suitablenitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite,a lower alkvl nitrite such as tert-butyl nitrite, or nitrosiumtetrafluoroborate in a suitable anhydrous solvent such as methyenechloride, THF, DMF, or acetonitrile with or without an amine base suchas pyridine or triethvlamine affords the compound of the formula XB.Alternatively, treatment of the deprotected thiol derived from compound39 with a stoichiometric quantity of sodium nitrite in aqueous oralcoholic acid affords the compound of the formula XB.

Nitro compounds of formula (X) wherein D₁, R_(e), R_(f), and p aredefined above and a nitrate containing ester is representative of the Dgroup as defined above may be prepared according to FIG. 30. The alcoholgroup of the formula 37 is converted to the ester of the formula 40wherein p, R_(e) and R_(f) are defined above and X is a halogen byreaction with an appropriate halide containing activated acylatingagent. Preferred methods for the formation of esters are reacting thealcohol with the preformed acid chloride or symmetrical anhydride of thehalide containing acid or condensing the alcohol and halide containingacid with a dehydrating agent such as DCC or EDAC HCl in the presence ofa catalyst such as DMAP or HOBt. Preferred halides are bromide andiodide. Reaction of the ester of the formula 40 with a suitablenitrating agent such as silver nitrate in an inert solvent such asacetonitrile affords the compound of the formula XC.

As noted above, another aspect of the invention provides a compositioncomprising (i) a therapeutically effective amount of at least one PDEinhibitor, which optionally can be substituted with at least one NO orNO₂ group or a group that stimulates endogenous production of NO or EDRFin vivo, and (ii) at least one compound that donates, transfers orreleases nitrogen monoxide as a charged species, i.e., nitrosonium (NO⁺)or nitroxyl (NO⁻), or as the neutral species, nitric oxide (NO•) and/orat least one compound that stimulates endogenous production of NC) orEDRF in vivo.

The compounds that donate, transfer or release nitric oxide or stimulateor elevate levels of endogenous EDRF can be any of those known to theart, including those mentioned and/or exemplified below.

Nitrogen monoxide can exist in three forms: NO⁻ (nitroxyl), NO• (nitricoxide) and NO⁺ (nitrosonium). NO• is a highly reactive short-livedspecies that is potentially toxic to cells. This is critical, becausethe pharmacological efficacy of NO depends upon the form in which it isdelivered. In contrast to NO•, nitrosonium and nitroxyl do not reactwith O₂ or O₂ ⁻ species. Consequently, administration of NO equivalentsdoes not result in the generation of toxic by-products or theelimination of the active NO moiety.

Compounds contemplated for use in the invention are nitric oxide andcompounds that release nitric oxide or otherwise directly or indirectlydeliver or transfer nitric oxide to a site of its activity, such as on acell membrane, in vivo. As used herein, the term “nitric oxide”encompasses uncharged nitric oxide (NO•) and charged nitric oxidespecies, particularly including nitrosonium ion (NO⁺) and nitroxyl ion(NO⁻). The reactive form of nitric oxide can be provided by gaseousnitric oxide. The nitric oxide releasing, delivering or transferringcompounds, having the structure F-NO wherein F is a nitric oxidereleasing, delivering or transferring moiety, include any and all suchcompounds which provide nitric oxide to its intended site of action in aform active for their intended purpose. As used herein, the term “NOadducts” encompasses any of such nitric oxide releasing, delivering ortransferring compounds, including, for example, S-nitrosothiols,S-nitrothiols, O-nitrosoalcohols, O-nitroalcohols, sydnonimines,2-hydroxy-2-nitrosohydrazines (NONOates),(E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides,nitrosoamines, as well a subtstates for the endogenous enzymes whichsynthesize nitric oxide. It is contemplated that any or all of these “NOadducts” can be mono- or poly-nitrosylated or nitrosated at a v arietyof naturally susceptible or artificially provided binding sites fornitric oxide or derivatives which donate or release NO.

One group of such NO adducts is the S-nitrosothiols, which are compoundsthat include at least one —S-NO group. Such compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andalso polyamino acids that do not possess an ascertained biologicalfunction, and derivatives thereof); S-nitrosylated amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures and derivatives thereof); S-nitrosylated sugars,S-nitrosylated modified and unmodified oligonucleotides (preferably ofat least 5, and more particularly 5-200 nucleotides); and anS-nitrosylated hydrocarbons where the hydrocarbon is a straight orbranched, saturated or unsaturated, aliphatic or aromatic hydrocarbon;S-nitrosylated hydrocarbons having one or more substituent groups inaddition to the S-nitroso group; and heterocyclic compounds.S-nitrosothiols and the methods for preparing them are described in U.S.Pat. No. 5,380,758; Oae et al., Org. Prep. Proc. Int., 15(3):165-198(1983); Loscalzo et al., J Pharmacol. Exp. Ther., 249(3):726729 (1989)and Kowaluk et al., J. Pharmacol. Exp. Ther., 256:1256-1264 (1990), thedisclosures of which are incorporated by reference herein in theirentirety.

One particularly preferred embodiment of this aspect relates toS-nitroso amino acids where the nitroso group is linked to a sulfurgroup of a sulfur-containing amino acid or derivative thereof. Suchcompounds include, for example, S-nitroso-N-acetylcysteine,S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine andS-nitroso-glutathione.

Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur group on an aminoacid or amino acid derivative thereof) from various functional classesincluding enzymes, such as tissue-type plasminogen activator (TPA) andcathepsin B; transport proteins, such as lipoproteins, heme proteinssuch as hemoglobin and serum albumin; and biologically protectiveproteins, such as the immunoglobulins and the cytokines. Suchnitrosylated proteins are described in WO 93/09806, the disclosure ofwhich is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where multiple thiol or othernucleophilic centers in the protein are modified.

Further examples of suitable S-nitrosothiols include the following:

(i) CH₃(C(R_(e))(R_(f)))_(x)SNO;

(ii) HS(C((R_(e))(R_(f)))_(x)SNO;

(iii) ONS(C(R_(e))(R_(f)))_(x)B; and

(iv) H₂N—CH(CO₂H)—(CH₂)_(x)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H

wherein x equals 2 to 20; R_(e) and R_(f) are defined above; and B is afluoro, a C₁-C₆ alkoxy, a cyano, a carboxamido, a cycloalkyl, anarylalkoxy, an alkylsulfinyl, an arylthio, an alkylamino, adialkylamino, a hydroxy, a carbamoyl, a N-alkylcarbamoyl, aN,N-dialkylcarbamoyl, an amino, a hydroxyl, a carboxyl, a hydrogen, anitro or an aryl.

Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) to yield the S-nitrosoderivative. Acids which may be used for this purpose include aqueoussulfuric, acetic acid and hydrochloric acid. Alternatively, theprecursor thiol may be nitrosylated by treatment with an alkyl nitritesuch as tert-butyl nitrite.

Another group of such NO adducts are those wherein the compounds donate,transfer or release nitric oxide and including compounds comprising atleast one ON—O—, ON—N— or ON—C— group. The compound that includes atleast one ON—N— or ON—C— group is preferably selected from the groupconsisting of ON-N— or ON—C— polvpeptides (the term “polypeptide”includes proteins and also polyamino acids that do not possess anascertained biological function, and derivatives thereof); ON—N— orON—C— amino acids (including natural and synthetic amino acids and theirstereoisomers and racemic mixtures); ON—N— or ON—C— sugars; ON—N— orON—C— modified and unmodified oligonucleotides (preferably of at least5, and more particularly 5-200 nucleotides), ON—O—, ON—N— or ON—C—hydrocarbons which can be branched or unbranched, saturated orunsaturated, aliphatic or aromatic hydrocarbons; ON—N— or ON—C—hydrocarbons having one or more substituent groups in addition to theON—N— or ON—C— group; and ON—N— or ON—C— heterocyclic compounds.

Another group of such NO adducts is the nitrites which have an —O—NOgroup wherein the organic template to which the nitrite group isappended is a protein, polypeptide, amino acid, carbohydrate, branchedor unbranched. saturated or unsaturated alkyl, aryl or heterocycliccompound. A preferred example is the nitrosylated form of isosorbide.Compounds in this group form S-nitrosothiol intermediates in vivo in therecipient human or other animal to be treated and can therefore includeany structurally analogous precursor R—O—NO of the S-nitrosothiolsdescribed above.

Another group of such adducts are nitrates which donate, transfer orrelease nitric oxide and include compounds comprising at least oneO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group. Preferred among these areO₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— polypeptides; O₂N—O—, O₂N—N—, O₂N—S— orON—C— amino acids; O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C—sugars; O₂N—O—,O₂N—N—, O₂N—S— or O₂N—C— modified and unmodified oligonucleotides;O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— hydrocarbons which can be branched orstraight, saturated or unsaturated, aliphatic or aromatic hydrocarbons;O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— hydrocarbons having one or moresubstituent groups in addition to the O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C—group; and O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— heterocyclic compounds.Preferred examples are isosorbide dinitrate and isosorbide mononitrate.

Another group of such NO adducts is the nitroso-metal compounds whichhave the structure (R)_(u)—A—M—(NO)_(v). R includes polypeptides (theterm “polypeptide” includes proteins and also polyamino acids that donot possess an ascertained biological function, and derivativesthereof); amino acids (including natural and synthetic amino acids andtheir stereoisomers and racemic mixtures and derivatives thereof);sugars; modified and unmodified oligonucleotides (preferably of at least5, and more particularly 5-200 nucleotides); and a hydrocarbon where thehydrocarbon can be branched or straight, saturated or unsaturated,aliphatic or aromatic hydrocarbon; hydrocarbons having one or moresubstituent groups in addition to the A-nitroso group; and heterocycliccompounds; A is S, O, or N; u and v are each independently an integer of1, 2 and 3, and M is a metal, preferably a transition metal. Preferredmetals include iron, copper, manganese, cobalt, selenium and luthidium.Also contemplated are N-nitrosylated metal centers such asnitroprusside.

Another group of such adducts are 2-hydroxy-2-nitrosohydrazines whichdonate, transfer or release nitric oxide and have a R₆₁R₆₂—N(O—M⁺)—NOgroup wherein R₆₁ and R₆₂ each independently include polypeptides, aminoacids, sugars, modified and unmodified oligonucleotides, hydrocarbonswhere the hydrocarbon can be branched or straight, saturated orunsaturated, aliphatic or aromatic hydrocarbon, hydrocarbons having oneor more substituent groups and heterocyclic compounds. M⁺ is a metalcation, such as, for example, a Group I metal cation.

Another group of such adducts are thionitrates which donate, transfer orrelease nitric oxide and have the structure R₆₁—S—NO₂ wherein R₆₁ is asdescribed above.

The present invention is also directed to compounds that stimulateendogenous svnthesis of NO or elevate levels of endogenousendothelium-derived relaxing factor (EDRF) in vivo. Such compoundsinclude, for example, L-arginine and OH-arginine, the substrates fornitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin,bisacodyl, phenolphthalein, and endothelin. EDRF is a vascular relaxingfactor secreted by the endothelium, and has been identified as nitricoxide (NO) or a closely related derivative thereof. (Palmer et al,Nature, 327:524-526 (1987), Ignarro et al, Proc. Natil. Acad. Sci. USA,84:9265-9269 (1987)).

When administered in vivo, the nitric oxides may be administered incombination with pharmaceutical carriers and in dosages describedherein.

The nitrosated or nitrosylated compounds of the invention are used atdose ranges and over a course of dose regimen and are administered inthe same or substantially equivalent vehicles/carrier by the same orsubstantially equivalent oral or nasal inhalant devices as theirnon-nitrosated or non-nitrosylated counterparts. The nitrosated ornitrosylated compounds of the invention can also be used in lower dosesand in less extensive regimens of treatment. The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used and whether thecompound is administered as part of a drug combination. Thus, the dosageregimen actually employed may X vary widely and therefore may deviatefrom the preferred dosage regimen set forth above.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from about 1 to about 100 mg/kg body weightdaily and more usually about 3 to 30 mg/kg. Dosage unit compositions maycontain such amounts of submultiples thereof to make up the daily dose.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more compounds which are known to be effective against thespecific disease state targeted for treatment. The compositions of theinvention can also be administered as described above or can be made toinclude one or more additional active compounds which are known to beeffective against the specific disease state is targeted for treatment.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of the ingredients of thepharmaceutical compositions of the invention. Associated with suchcontainer(s) can be a notice in the form prescribed by a governmentalagency regulating the manufacture, use or sale of pharmaceuticals orbiological products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

Each of the publications, patents and patent applications describedherein is hereby incorporated by reference herein in their entirety.

Various modifications of the invention, in addition to those describedherein, will be apparent to one skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims.

What is claimed is:
 1. A compound of structure IV:

wherein F is —CH₂— or sulfur; R₄ is (i) hydrogen, (ii)—CH(R_(d))—O—C(O)—Y—Z—(C(R_(e))(R_(f)))_(p)—T—Q, (iii)—C(O)—T—(C(R_(e))R_(f)))_(p)—TR—Q, or (iv)—C(O)—Z—(G—(C(R_(e))(R_(f)))_(p)—T—Q)_(p); wherein R_(d) is a hydrogen,a lower alkyl, a cycloalkyl, an aryl, an arylalkyl, or a heteroaryl; Yis oxygen, sulfur, CH₂ or NR_(i), wherein R_(i) is a hydrogen or a loweralkyl; R_(e) and R_(f) are each independently a hydrogen, a lower alkyl,a haloalkyl, an alkoxy, a cycloalkyl, an aryl, a heteroaryl, anarylalkyl, an amino, an alkylamino, an amido, an alkylamido, adialkylamino, a carboxylic acid, a carboxylic ester, a carboxamido or—T—Q, or R_(e) and R_(f) taken together with the carbons to which theyare attached are a carbonyl, a cycloalkyl, a heterocyclic ring or abridged cycloalkyl; p is an integer from 1 to 10; T is independently acovalent bond, oxygen, sulfur or NH; G is a covalent bond, —T—C(O)—,—C(O)—T— or T; Z is a covalent bond, a lower alkyl, a haloalkyl, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, a heteroalkyl, anarylheterocyclic ring or (C(R_(e))(R_(f)))_(p); and Q is —NO or —NO₂;and R₈ is a hydrogen or a lower alkyl; and R₁₃ is:

R₆ and R₇ are each independently a hydrogen or R₄, wherein R₄ is asdefined above; with the proviso that at least one of R₄, R₆ or R₇contains at least one —NO or —NO₂, group.
 2. The compound of claim 1,wherein the compound of structure IV is a nitrosated ICI 153,110, anitrosylated ICI 153,110, a nitrosated and nitrosylated ICI 153,110, anitrosated motapizone, a nitrosylated motapizone, a nitrosated andnitrosylated motapizone, a nitrosated pimobenden, a nitrosylatedpimobenden, a nitrosated and nitrosylated pimobenden, a nitrosatedsiguazodan, a nitrosylated siguazodan, a nitrosated and nitrosylatedsiguazodan, a nitrosated imazodan, a nitrosylated imazodan, a nitrosatedand nitrosylated imazodan, a nitrosated CI 930, a nitrosylated CI 930, anitrosated and nitrosylated CI 930, a nitrosated4,5-dihydro-5-methyl-6-[4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinone,a nitrosylated4,5-dihydro-5-methyl-6-[4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinone,a nitrosated and nitrosylated4,5-dihydro-5-methyl-6-[4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinone,a nitrosated EMD 53998, a nitrosylated EMD 53998 or a nitrosated andnitrosylated EMD
 53998. 3. A composition comprising the compound ofclaim 1 and a pharmaceutically acceptable carrier.
 4. A method fortreating a sexual dysfunction in an individual in need thereofcomprising administering to the individual a therapeutically effectiveamount of the composition of claim 3 to treat the sexual dysfunction. 5.The method of claim 4, wherein the individual is female.
 6. The methodof claim 4, wherein the individual is male.
 7. A composition comprisingthe compound of claim 1 and a compound that donates, transfers orreleases nitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase.
 8. Thecomposition of claim 7, wherein the compound that donates, transfers orreleases nitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase is presentin a one to ten fold molar excess with respect to the compound ofstructure IV.
 9. The composition of claim 7, wherein the compound thatdonates, transfers or releases nitrogen monoxide donates, transfers orreleases nitrogen monoxide as at least one of NO⁺, NO⁻ or NO•.
 10. Thecomposition of claim 7, wherein the compound that donates, transfers orreleases nitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase is anS-nitrosothiol.
 11. The composition of claim 10, wherein theS-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione. 12.The composition of claim 10, wherein the S-nitrosothiol is: (i)CH₃(C(R_(e))(R_(f)))_(x)SNO; (ii) HS(C((R_(e))(R_(f)))_(x)SNO; (iii)ONS(C(R_(e))(R_(f)))_(x)B; or (iv)H₂N—CH(CO₂H)—(CH₂)_(x)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein xequals 2 to 20; R_(e) and R_(f) are independently a hydrogen, a loweralkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylic ester, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, an alkylamino, adialkylamino, or —T—Q, or R_(e) and R_(f) taken together with the carbonatoms to which they are attached are a carbonyl, a heterocyclic ring, acycloalkyl or a bridged cycloalkyl; T is a covalent bond, oxygen, sulfuror nitrogen, Q is NO or NO₂, and B is a fluoro, an alkoxy, a cyano, acarboxamido, a cycloalkyl, an arylalkoxy, an alkylsulfinyl, an arylthio,an alkylamino, a dialkylamino, a hydroxy, a carbamoyl, anN-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an amino, a hydroxyl, acarboxyl, a hydrogen, a nitro or an aryl.
 13. The composition of claim7, wherein the compound that donates, transfers or releases nitrogenmonoxide, induces the production of endogenous endothelium-derivedrelaxing factor, stimulates endogenous synthesis of nitrogen monoxide oris a substrate for nitric oxide synthase is L-arginine or OH—arginine.14. The composition of claim 7, wherein the compound that donates,transfers or releases nitrogen monoxide, induces the production ofendogenous endothelium-derived relaxing factor, stimulates endogenoussynthesis of nitrogen monoxide or is a substrate for nitric oxidesynthase is: (i) a compound comprising at least one ON—O—, ON—N— orON—C— group; (ii) a nitroso-metal compound having the structure(R)_(u)—A—M—(NO)_(v), wherein R is a polypeptide, an amino acid, asugar, an oligonucleotide, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromatichydrocarbon, or a heterocyclic compound; A is S, O or N; u and v areeach independently an integer of 1, 2 or 3; and M is a transition metal;(iii) a compound having the structure R₆₁R₆₂—N—(O—M⁺)—NO, wherein R₆₁and R₆₂ are each independently a polypeptide, an amino acid, a sugar, anoligonucleotide, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic hydrocarbon, or aheterocyclic compound; and M⁺ is a metal cation; or (iv) a thionitratehaving the structure R₆₁—S—NO₂, wherein R₆₁ is as defined above.
 15. Thecomposition of claim 14, wherein the compound comprising at least oneON—O—, ON—N— or ON—C— group is an ON—N-polypeptide, an ON—C-polypeptide,an ON—N-amino acid, an ON—C-amino acid, an ON—C-sugar, an ON—N-sugar, anON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic ON—N-hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticON—C-hydrocarbon, a straight or branched, saturated or unsaturated,aliphatic or aromatic ON—O-hydrocarbon, an ON—N-heterocyclic compound,or an ON—C-heterocyclic compound.
 16. The composition of claim 7,wherein the compound that donates, transfers or releases nitrogenmonoxide, induces the production of endogenous endothelium-derivedrelaxing factor, stimulates endogenous synthesis of nitrogen monoxide oris a substrate for nitric oxide synthase is a compound comprising atleast one O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group.
 17. The composition ofclaim 16, wherein the compound comprising at least one O₂N—O—, O₂N—N—,O₂N—S— or O₂N—C— group is an O₂N—O-polypeptide, an O₂N—N-polypeptide, anO₂N—S-polypeptide, an O₂N—C-polypeptide, an O₂N—O-amino acid, anO₂N—N-amino acid, an O₂N—S-amino acid, an O₂N—C-amino acid, anO₂N—O-sugar, an O₂N—N-sugar, an O₂N—S-sugar, an O₂N—C-sugar, anO₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic O₂N—O-hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticO₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated,substituted or unsubstituted, aliphatic or aromatic O₂N—S-hydrocarbon, astraight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic O₂N—C-hydrocarbon, anO₂N—O-heterocyclic compound, an O₂N—N-heterocyclic compound, anO₂N—S-heterocyclic compound or an O₂N—C-heterocyclic compound.
 18. Amethod for treating a sexual dysfunction in an individual in needthereof comprising administering to the individual a therapeuticallyeffective amount of the composition of claim 7 to treat the sexualdysfunction.
 19. The method of claim 18, wherein the individual isfemale.
 20. The method of claim 18, wherein the individual is male. 21.A kit comprising the compound of claim
 1. 22. The kit of claim 21,further comprising a compound that donates, transfers or releasesnitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase.
 23. A kitcomprising the composition of claim
 7. 24. A method for treating asexual dysfunction in an individual in need thereof comprisingadministering a therapeutically effective amount of a phosphodiesteraseinhibitor of structure IV, and a compound that donates, transfers orreleases nitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase, whereinthe phosphodiesterase inhibitor of structure IV is:

wherein F is —CH₂— or sulfur; R₈ is a hydrogen or a lower alkyl; R₁₃ is:

and R₄, R₆ and R₇ are hydrogen.
 25. The method of claim 24, wherein theindividual is female.
 26. The method of claim 24, wherein the individualis male.
 27. The method of claim 24, wherein the compound that donates,transfers or releases nitrogen monoxide, induces the production ofendogenous endothelium-derived relaxing factor, stimulates endogenoussynthesis of nitrogen monoxide or is a substrate for nitric oxidesynthase is present in a one to ten fold molar excess with respect tothe phosphodiesterase inhibitor of structure IV.
 28. The method of claim24, wherein the compound that donates, transfers or releases nitrogenmonoxide donates, transfers or releases nitrogen monoxide as at leastone of NO⁺, NO⁻ or NO•.
 29. The method of claim 24, wherein the compoundthat donates, transfers or releases nitrogen monoxide, induces theproduction of endogenous endothelium-derived relaxing factor, stimulatesendogenous synthesis of nitrogen monoxide or is a substrate for nitricoxide synthase is an S-nitrosothiol.
 30. The method of claim 29, whereinthe S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione. 31.The method of claim 29, wherein the S-nitrosothiol is: (i)CH₃(C(R_(e))(R_(f)))_(x)SNO; (ii) HS(C((R_(e))(R_(f)))_(x)SNO; (iii)ONS(C(R_(e))(R_(f)))_(x)B; or (iv)H₂N—CH(CO₂H)—(CH₂)_(x)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H; wherein xequals 2 to 20; R_(e) and R_(f) are independently a hydrogen, a loweralkyl, a haloalkyl, an alkoxy, a carboxylic acid, a carboxylic ester, acycloalkyl, an aryl, a heteroaryl, an arylalkyl, an alkylamino, adialkylamino, or —T—Q, or R_(e) and R_(f) taken together with the carbonatoms to which they are attached are a carbonyl, a heterocyclic ring, acycloalkyl or a bridged cycloalkyl; T is a covalent bond, oxygen, sulfuror nitrogen, Q is NO or NO₂, and B is a fluoro, an alkoxy, a cyano, acarboxamido, a cycloalkyl, an arylalkoxy, an alkyl sulfinyl, anarylthio, an alkylamino, a dialkylamino, a hydroxy, a carbamoyl, anN-alkylcarbamoyl, an N,N-dialkylcarbamoyl, an amino, a hydroxyl, acarboxyl, a hydrogen, a nitro or an aryl.
 32. The method of claim 24,wherein the compound that donates, transfers or releases nitrogenmonoxide, induces the production of endogenous endothelium-derivedrelaxing factor, stimulates endogenous synthesis of nitrogen monoxide oris a substrate for nitric oxide synthase is L-arginine or OH-arrginine.33. The method of claim 24, wherein the compound that donates, transfersor releases nitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase is: (i) acompound comprising at least one ON—O—, ON—N— or ON—C— group; (ii) anitroso-metal compound having the structure (R)_(u)-A-M-(NO)_(v),wherein R is a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic hydrocarbon, or a heterocycliccompound; A is S, O or N; u and v are each independently an integer of1, 2 or 3; and M is a transition metal; (iii) a compound having thestructure R₁₆R₆₂—N—(O—M⁺)—NO, wherein R₆₁, and R₆₂ are eachindependently a polypeptide, an amino acid, a sugar, an oligonucleotide,a straight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic hydrocarbon, or a heterocycliccompound; and M⁺ is a metal cation; or (iv) a thionitrate having thestructure R₆₁—S—NO₂, wherein R₆₁ is as defined above.
 34. The method ofclaim 33, wherein the compound comprising at least one ON—O—, ON—N— orON—C— group is an ON—N-polypeptide, an ON—C-polypeptide, an ON—N-aminoacid, an ON—C-amino acid, an ON—C-sugar, an ON—N-sugar, anON—N-oligonucleotide, an ON—C-oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic ON—N-hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticON—C-hydrocarbon, a straight or branched, saturated or unsaturated,aliphatic or aromatic ON—O-hydrocarbon, an ON—N-heterocyclic compound,or an ON—C-heterocyclic compound.
 35. The method of claim 27, whereinthe compound that donates, transfers or releases nitrogen monoxide,induces the production of endogenous endothelium-derived relaxingfactor, stimulates endogenous synthesis of nitrogen monoxide or is asubstrate for nitric oxide synthase is a compound comprising at leastone O₂N—O—, O₂N—N—, O₂N—S— or O₂N—C— group.
 36. The method of claim 35,wherein the compound comprising at least one O₂N—O—, O₂N—N—, O₂N—S— orO₂N—C— group is an O₂N—O-polypeptide, an O₂N—N-polypeptide, anO₂N—S-polypeptide, an O₂N—C-polypeptide, an ON—O-amino acid, anO₂N—N-amino acid, an O₂N—S-amino acid, an O₂N—C-amino acid, anO₂N—O-sugar, an O₂N—N-sugar, an O₂N—S-sugar, an O₂N—C-sugar, anO₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic O₂N—O-hydrocarbon, a straight or branched, saturated orunsaturated, substituted or unsubstituted, aliphatic or aromaticON—N-hydrocarbon, a straight or branched, saturated or unsaturated,substituted or Uninsubstituted, aliphatic or aromatic O₂N—S-hydrocarbon,a straight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic O₂N—C-hydrocarbon, anO₂N—O-heterocyclic compound, an O₂N—N-heterocyclic compound, anO₂N—S-heterocyclic compound or an O₂N—C-heterocyclic compound.
 37. Themethod of claim 24, wherein the phosphodiesterase inhibitor of structureIV is ICI 153,110, motapizone, pimobenden, siguazodan, imazodan, CI 930,nitrosated4,5-dihydro-5-methyl-6-[4-(4-oxo-1(4H)-pyridinyl)phenyl)-3(2H)-pyridazinoneor EMD
 53998. 38. The method of claim 24, further comprisingadministering a pharmaceutically acceptable carrier.
 39. The method ofclaim 24, wherein the phosphodiesterase inhibitor of structure IV andthe compound that donates, transfers or releases nitrogen monoxide,induces the production of endogenous endothelium-derived relaxingfactor, stimulates endogenous synthesis of nitrogen monoxide or is asubstrate for nitric oxide synthase are administered in the form of acomposition.
 40. The method of claim 24, wherein the phosphodiesteraseinhibitor of structure IV and the compound that donates, transfers orreleases nitrogen monoxide, induces the production of endogenousendothelium-derived relaxing factor, stimulates endogenous synthesis ofnitrogen monoxide or is a substrate for nitric oxide synthase areadministered separately.
 41. The method of claim 24, wherein thephosphodiesterase inhibitor of structure IV and the compound thatdonates, transfers or releases nitrogen monoxide, induces the productionof endogenous endothelium-derived relaxing factor, stimulates endogenoussynthesis of nitrogen monoxide or is a substrate for nitric oxidesynthase are administered orally.